Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring-Size Modifications in the Quinuclidine Moiety.

Six highly enantiopure analogues of [2.2.2] were synthesized with five- or seven-membered rings in the (original) quinuclidine skeleton. Five of these compounds were prepared through epoxide opening by a secondary cyclic amine, providing the nor- and homoquinuclidine moieties through five- and six-membered ring formation. This method failed in the case of seven-membered ring formation, so for that particular ring size a different synthetic route starting from 3-quinuclidone was applied. The six novel analogues were examined as organocatalysts in four asymmetric conjugate addition reactions and the results compared with those of known cinchona alkaloid catalysts. This study shows that modification of the quinuclidine ring can have a substantial influence on catalyst activity and enantioselectivity. To acquire more insight into the characteristics of the new catalysts, the pKaH values were determined by means of fluorescence spectroscopy. Furthermore, relative reaction rates of conjugate thiol additions reactions catalyzed by these quinidine analogues were measured through polarimetry.

Organocatalytic enantioselective Pictet-Spengler approach to biologically relevant 1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids.

A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.

Cinchona Alkaloid Catalyzed Sulfa-Michael Addition Reactions Leading to Enantiopure ß-Functionalized Cysteines.

Sulfa-Michael additions to α,ß-unsaturated N-acylated oxazolidin-2-ones and related α,ß-unsaturated α-amino acid derivatives have been enantioselectively catalyzed by Cinchona alkaloids functionalized with a hydrogen bond donating group at the C6' position. The series of Cinchona alkaloids includes known C6' (thio)urea and sulfonamide derivatives and several novel species with a benzimidazole, squaramide or a benzamide group at the C6' position. The sulfonamides were especially suited as bifunctional organocatalysts as they gave the products in very good diastereoselectivity and high enantioselectivity. In particular, the C6' sulfonamides catalyzed the reaction with the α,ß-unsaturated α-amino acid derivatives to afford the products in a diastereomeric ratio as good as 93:7, with the major isomer being formed in an ee of up to 99%. The products of the organocatalytic sulfa-Michael addition to α,ß-unsaturated α-amino acid derivatives were subsequently converted in high yields to enantiopure ß-functionalized cysteines suitable for native chemical ligation.

Organocatalytic enantioselective Pictet-Spengler reactions for the syntheses of 1-substituted 1,2,3,4-tetrahydroisoquinolines.

A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet-Spengler reactions. The sulfenamide moiety is crucial for the rate and enantioselectivity of the iminium ion cyclization and the products are readily recrystallized to high enantiomeric purity. Using this methodology we synthesized the natural products (R)-crispine A, (R)-calycotomine and (R)-colchietine, the synthetic drug (R)-almorexant and the (S)-enantiomer of a biologically active (R)-AMPA-antagonist.

Enantioselective BINOL-phosphoric acid catalyzed Pictet-Spengler reactions of N-benzyltryptamine.

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.

Total Synthesis of Aquatolide.

A total synthesis of the sesquiterpene lactone aquatolide has been accomplished. The central step is an intramolecular [2 + 2]-photocycloaddition of an allene onto an α,ß-unsaturated δ-lactone. Other key steps are an intramolecular Horner-Wadsworth-Emmons reaction to close the lactone and an intramolecular Mukaiyama-type aldol reaction to cyclize the eight-membered ring. Racemic aquatolide has been resolved using preparative HPLC.

A chemical ionization study of deuteron transfer initiated propene loss from propoxypyridines.

The mechanism of propene loss from the metastable [M + D](+) ions of isomeric 2-, 3-, and 4-n-propoxypyridines and the related isopropoxypyridines has been examined by chemical ionization (CI) and tandem mass spectrometry in combination with deuterium labeling. The [M + D](+) ions were generated with CD(3)OD, CD(3)CN, (CD(3))(2)CO, or pyrrole-D(5) (listed in order of increasing proton affinity) as the CI reagent. The results reveal that the deuteron added in the CI process is not interchanged with the hydrogen atoms of the propyl group prior to propene loss from the metastable [M + D](+) ions of the propoxypyridines. The site selective labeling of the alpha-, beta-, or gamma-position of the propyl group indicates that the [M + D](+) ions of 2-n-propoxypyridine expel propene with formation of an ion-neutral complex composed of a propyl carbenium ion and 2-pyridone. By contrast, the [M + D](+) ions of 3-n-propoxypyridine expel propene by: (1) Formation of ion-neutral complexes, and (2) a conventional 1,5-hydride shift from the beta-position of the n-propyl group to the ring and/or a 1,2-elimination type process. For the 4-isomer, the results suggest the occurrence of propene loss by a 1,2-elimination in addition to the intermediate formation of ion-neutral complexes. Loss of propene with one deuterium atom is the only reaction of the [M + D](+) ions of the isopropoxypyridines labeled at the alpha-position of the isopropyl group. The results for the isopropoxypyridines labeled with three deuterium atoms at the beta-position are consistent with: (1) The loss of propene by ion-neutral complex formation and the occurrence of a substantial isotope effect in the subsequent proton/deuteron transfer within the complex, and/or (2) the loss of propene by a 1,2-elimination type reaction.

Electron capture and collisionally activated dissociation mass spectrometry of doubly charged hyperbranched polyesteramides.

Electron capture dissociation (ECD) of doubly protonated hyperbranched polyesteramide oligomers (1100-1900 Da) was examined and compared with the structural information obtained by low energy collisionally activated dissociation (CAD). Both the ester and amide bonds of the protonated species were cleaved easily upon ECD with the formation of odd electron (OE(.+)) or even electron (EE(+)) fragment ions. Several mechanistic schemes are proposed that describe the complex ECD fragmentation behavior of the multiply charged oligomers. In contrast to studies of biomolecules, the present results indicate that consecutive cleavages induced by intramolecular H-shifts are significant for ECD and of less importance for low energy CAD. The capture of an electron by the ionized species results in fragmentation associated with a redistribution of the excess internal energy over the products and the subsequent bond cleavage. Low energy, multiple collision CAD is found to be a more selective dissociation method than ECD in view of the observation that only amide bonds are cleaved for most of the hyperbranched polymers examined with CAD in this study. ECD appears not to provide complementary structural information compared to CAD in the study of hyperbranched polymers, even though a significantly more complex ECD fragmentation behavior is observed. ECD is shown to be of use for the structural characterization of large oligomers that may not dissociate upon low energy CAD. This is a direct result of the fact that ECD produces ionized hyperbranched oligomers with a relatively high internal energy.

Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet-Spengler reaction.

The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-ß-carboline ring and (ii) a Pd-catalysed Tsuji-Trost allylic alkylation, closing the D-ring.

Non-Equilibrium Isomer Distribution of the Gas-Phase Photoactive Yellow Protein Chromophore.

The conjugate base of para-coumaric acid, which can be conveniently generated in the gas phase by electrospray ionization (ESI), is a commonly used model system for the chromophore of the photoactive yellow protein. Here we report its gas-phase IR spectrum, which shows that the anion easily adopts a carboxylate structure lying 60 kJ/mol higher in energy than the global minimum phenoxide structure. Generation of the biologically more relevant phenoxide isomer by ESI can be achieved using dry acetonitrile as solvent.

Synthesis of strained cyclic peptides via an aza-Michael-acyl-transfer reaction cascade.

A new method is presented to prepare strained lactams. Esterification of the C-terminus of a dipeptide with ß-nitrostyrene or quinoline-type auxiliaries is followed by lactam formation by an intramolecular aza-Michael-acyl-transfer reaction cascade. Ultimately, the cyclic tetrapeptide cyclo[Phe-Tyr-Ala-Gly] has been prepared.

Reactions of (di)manganese carbonyl ions with 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3TACN) in the gas phase.

The gas-phase reactions of a series of (di)manganese carbonyl positive ions with 1,4,7-trimethyl-1,4,7-triazacyclononane (Me(3)TACN) have been examined with the aid of Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. The monomanganese carbonyl ions, [Mn(CO)(n)](+) (n = 2-5), react predominantly by ligand exchange and to a minor extent by electron transfer with the formation of the radical cation of Me(3)TACN. For the [Mn(CO)(n)](+) (n = 2-4) ions, the ligand exchange results in the exclusive formation of a [Mn(Me(3)TACN)](+) complex, whereas small amounts of [Mn(CO)(Me(3)TACN)](+) ions are also generated in the reactions of the [Mn(CO)(5)](+) ion. The [Mn(2)(CO)(n)](+) ions (n = 2, 4 and 5) react also by competing electron transfer and ligand exchange. The reaction of the [Mn(2)(CO)(2)](+) and [Mn(2)(CO)(4)](+) ions is associated with cleavage of the Mn--Mn bond as evidenced by the pronounced formation of [Mn(Me(3)TACN)](+) ions. For [Mn(2)(CO)(5)](+), the ligand exchange leads mainly to the formation of [Mn(2)(CO)(n)(Me(3)TACN)](+) (n = 1-3) ions. These primary product ions react subsequently by the incorporation of a second Me(3)TACN molecule to afford [Mn(2)(CO)(Me(3)TACN)(2)](+) and [Mn(2)(CO)(2)(Me(3)TACN)(2)](+) ions. Both of these latter species incorporate an oxygen molecule with formation of ions with the assigned composition of [Mn(2)(O(2))(CO)(Me(3)TACN)(2)](+) and [Mn(2)(O(2))(CO)(2)(Me(3)TACN)(2)](+).

Horseradish peroxidase-catalyzed oligomerization of ferulic acid on a template of a tyrosine-containing tripeptide.

Ferulic acid (FA) is an abundantly present phenolic constituent of plant cell walls. Kinetically controlled incubation of FA and the tripeptide Gly-Tyr-Gly (GYG) with horseradish peroxidase and H2O2 yielded a range of new cross-linked products. Two predominant series of hetero-oligomers of FA linked by dehydrogenation to the peptidyl tyrosine were characterized by electrospray ionization (tandem) mass spectrometry. One series comprises GYG coupled with 4-7 FA moieties linked by dehydrogenation, of which one is decarboxylated. In the second series 4-9 FA moieties linked by dehydrogenation, of which two are decarboxylated, are coupled to the tripeptide. A third series comprises three hetero-oligomers in which the peptidyl tyrosine is linked to 1-3 FA moieties of which none is decarboxylated. Two mechanisms for the formation of the FA-Tyr oligomers that result from the dualistic, concentration-dependent chemistry of FA and their possible role in the regulation of plant cell wall tissue growth are presented.